The microenvironment of nerve cells in the mammalian brain is composed of intercellular channels which can be visualized directly with the electron microscope. The tissue volume of these channels and their capacity to transport catecholamines have been shown to decrease as a function of chronological age in the rat. We propose here a correlated biochemical and ultrastructure analysis of these age-associated changes in the neuronal microenvironment and their histophysiological implications to the aging brain. The constituent protein-proteoglycan complexes and glycoproteins of the cerebral cortex and corpus striatum of immature, mature, and senescent rats will be analyzed chemically and correlated by means of electron microscopic histochemistry with the contents of the intercellular channels. These carbohydrate-containing macromolecules will be biochemically analyzed with regard to their substituent acid glycosaminoglycans and simple glycoproteins. Their cellular origin from neurons and neuroglia will be followed in tissue cultures from immature, mature and senescent animals. Intracellular synthesis, metabolic turnover, assembly by cytoplasmic organelles, and mechanisms of intracellular transport as a function of chronological aging will be investigated by a closely correlated ultrastructural and biochemical analysis of neuronal subcellular fractions.